In scientific circles, the Y chromosome -- the essence of masculinity -- is scorned as the runt of the human genetic family, so henpecked by mutations that it is wasting away.
So little respect does this small, self-absorbed chromosome command that scientists investigating the human genome felt free to jeer or mostly ignore it -- until now.
In research made public Wednesday, scientists confessed that they have sorely misjudged this single-minded sex specialist. After six years of laboratory work, scientists at the Whitehead Institute for Biomedical Research in Cambridge, Mass., and the Washington University School of Medicine in St. Louis presented the complete genetic sequence of the Y chromosome, the first human chromosome to be thoroughly decoded.
They revealed that the tiny chromosome responsible for the male of the species is more subtle, robust and complex than previously believed. It has a unique way of keeping its indispensable genes intact, they found, that sidesteps the conventional genetic shuffling on which all other chromosomes depend.
Their discoveries are prompting researchers to rethink the genetic basis for the myriad differences between men and women in anatomy, physiology, cognition, behavior and disease susceptibility. There is an order to what had seemed to so many researchers before to be relentless decay. The DNA that many had dismissed as junk has genetic meaning, the researchers said.
The Y chromosome harbors up to three times as many genes as commonly thought, the researchers determined. Moreover, it is evolving in an unconventional way at a speed that no one had imagined.
“The Y has been admired; it has been reviled; it has been considered the root of all evil. It has certainly been misunderstood,” said Francis Collins, director of the National Human Genome Research Institute. “To have all its instructions laid out in front of us is a very significant moment in the history of biology.”
The findings, detailed in two research papers published today in the scientific journal Nature, upset some basic assumptions about the molecular biology of sex.
“It knocked me out of my chair the first time I heard it,” said Brandeis University biologist James Haber, who studies how genes reproduce and repair themselves.
The relationship between the Y chromosome, which triggers male development in an embryo, and the X chromosome, which is responsible for female development, is a mystery that has been unfolding for more than 240 million years.
In nature’s first experiments with sex, the male Y and female X chromosomes started on an equal footing. They evolved from ordinary chromosomes between 240 million and 320 million years ago, research suggests.
In the ages since, they have gone quite separate ways.
The X chromosome today dwarfs its dwindling male counterpart. Indeed, nearly half of all genes related to the earliest stages of sperm production reside not on the male sex chromosome as might be expected, but on the female chromosome.
In all, there are 46 human chromosomes. In women, they are mated in 23 matching pairs. Through sexual recombination, when sperm and egg are created, the regular chromosomes and the X chromosome draw on their matching counterparts for genetic repairs. The Y is the exception.
Only when a male is conceived do the genes on the Y chromosome come into play.
It is the only chromosome present in one sex and not the other. In addition to 22 matching pairs in men, the Y is paired, not with its twin, but with the X chromosome.
The Y is a reluctant partner. Unlike all other chromosomes, it shares only a fraction of its DNA. Until now, researchers were convinced that the Y chromosome had no way to repair any defective genes or rid itself of mutations, including those that cause disease, mental illness or male infertility.
But in perhaps the most intriguing new finding, Whitehead biologist David Page, who led the consortium of research teams, and his colleagues discovered that the male chromosome evolved its own way of repairing itself.
Almost all of the Y genes are concealed in eight long sentences of DNA characters that read the same forward and backward, stretching for thousands of all but indecipherable genetic base pairs.
Geneticists call these unusual strings of DNA “palindromes” -- after the literary parlor game that spawned phrases such as “Madam I’m Adam.”
The DNA palindromes on the Y chromosome are the most extensive mirror sequences known in any species. The longest is almost 3 million characters long and is 99.97% identical.
Until now, scientists saw all this repetitive DNA as evidence that the Y chromosome was a genetic junkyard.
In an abrupt reversal of scientific fortune, researchers are now convinced that this repeated DNA is the key to the survival of the male chromosome. The Y actually has less genetic junk than any other part of the human genome, Page and his colleagues said Wednesday.
For the Y chromosome, these extensive repetitive stretches of gene sequences serve as templates to repair and proofread its own DNA, almost as if each were a gene on a separate matching chromosome.
The male chromosome checks its appearance in the reflection of these DNA mirror images, to eliminate potentially harmful mutations.
By comparing the human Y chromosome sequence with parts of the chimpanzee male chromosome, researchers deduced that this self-repair mechanism has been in use for at least 5 million years.
“To me, this is the single most shocking thing we have learned about the Y,” Page said. “It is completely unexpected. It highlights how inventive nature has been.”
These palindromes also made the task of sequencing the DNA of the Y chromosome extremely difficult, said Richard Wilson, director of the genome sequencing center at Washington University, which pieced together the strings of virtually identical DNA. “It is like a hall of mirrors,” he said. “You might only see only one [DNA] difference in 10,000 base pairs.”
No other species has had its male sex chromosome analyzed in such detail.
In all, the Y chromosome contains 78 genes, the researchers discovered.
Most of them are involved in reproduction and sex determination, but some play housekeeping roles in the life of healthy human cells throughout the body.
Even so, the Y chromosome does continue to change as it passes from one generation to the next. That surprised those who considered the structure of the Y chromosome as constant as a man’s refusal to ask a stranger for directions.
“The Y chromosome is probably one of the most dynamic chromosomes in the human genome,” said Evan Eichler at Case Western Reserve University in Cleveland, who studies how genes duplicate and repair themselves.
Every time a son is born, the chromosome that makes him male is altered by about 600 base pairs of DNA, the researchers calculated -- a rate of change that Eichler called “astounding.”
So far, researchers have analyzed only one man’s Y chromosome. As others come under detailed scrutiny, Page and his colleagues expect to uncover considerable variation from one man to the next.
“It says that our genome is changing all the time,” said Huntington Willard, director of Duke University’s Institute for Genome Sciences and Policy. “Evolution is happening now, not just in the distant past.”